title: AC1MMYR2, an inhibitor of dicer-mediated biogenesis of Oncomir miR-21, reverses epithelial-mesenchymal transition and suppresses tumor growth and progression.
abstract: The extensive involvement of miRNAs in cancer pathobiology has opened avenues for drug development based on oncomir inhibition. Dicer is the core enzyme in miRNA processing that cleaves the terminal loop of precursor microRNAs (pre-miRNAs) to generate mature miRNA duplexes. Using the three-dimensional structure of the Dicer binding site on the pre-miR-21 oncomir, we conducted an in silico high-throughput screen for small molecules that block miR-21 maturation. By this method, we identified a specific small-molecule inhibitor of miR-21, termed AC1MMYR2, which blocked the ability of Dicer to process pre-miR-21 to mature miR-21. AC1MMYR2 upregulated expression of PTEN, PDCD4, and RECK and reversed epithelial-mesenchymal transition via the induction of E-cadherin expression and the downregulation of mesenchymal markers, thereby suppressing proliferation, survival, and invasion in glioblastoma, breast cancer, and gastric cancer cells. As a single agent in vivo, AC1MMYR2 repressed tumor growth, invasiveness, and metastasis, increasing overall host survival with no observable tissue cytotoxicity in orthotopic models. Our results offer a novel, high-throughput method to screen for small-molecule inhibitors of miRNA maturation, presenting AC1MMYR2 as a broadly useful candidate antitumor drug.
authors.affiliation: Tianjin Medical University General Hospital, 154, Anshan Road, Heping, Tianjin 300052, China.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Shi
authors.forename: Junxia
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Qian
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.forename: Kailiang
authors.initials: K
authors.lastname: Zhang
authors.forename: Luyue
authors.initials: L
authors.lastname: Chen
authors.forename: Jilong
authors.initials: J
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Anling
authors.initials: A
authors.lastname: Zhang
authors.forename: Peiyu
authors.initials: P
authors.lastname: Pu
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics; D054852:Small Molecule Libraries; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C584580:AC1MMYR2 compound; D000970:Antineoplastic Agents; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D011743:Pyrimidines; D012333:RNA, Messenger; D054852:Small Molecule Libraries; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases